Constitutional and acquired autosomal aneuploidy

Abstract

Chromosomal imbalances can result from numerical or structural anomalies. Numerical chromosomal abnormalities are often referred to as aneuploid conditions. This article focuses on the occurrence of constitutional and acquired autosomal aneuploidy in humans. Topics covered include frequency, mosaicism, phenotypic findings, and etiology. The article concludes with a consideration of anticipated advances that might allow for the development of screening tests and/or lead to improvements in our understanding and management of the role that aneuploidy plays in the aging process and acquisition of age-related and constitutional conditions.

Figure 1. Methods for evaluating sperm chromosomal complements

Hamster-egg/human sperm in vitro culture methodology allows one to directly observe chromosomes, as illustrated in this figure (a) which shows QFQ-banded chromosomes from a sperm having a female haploid complement (23,X). Studies using FISH methodology on sperm nuclei allow for estimation of aneuploidy frequencies based on targeted loci (usually pericentromeric sequences). In panel (b) sperm nuclei are shown following FISH with probes for chromosomes X (DXZ1; green); Y (DYZ3; red); 17 (D17Z1; yellow); and 18 (D18Z1; aqua). This field shows 2 sperm with a female complement, 4 sperm with a male complement; and 1 sperm (arrow) having an extra sex chromosome (inferred to be 24,XY) [panel b figure was prepared by Nurcan Gursoy].

Figure 2. Achiasmate chromosomes may engage in distributive pairing

In Drosophila, there is evidence that a lack of meiotic recombination leads to non-exchange pairing, with distributive pairing preferentially occurring between chromosomes that are similar in size. In humans it is not known if distributive pairing occurs, but one could speculate that the observed perturbations in recombination could result in distributive pairing. If this occurs between homologs it could lead to a balanced gamete; if it occurs between nonhomologs it could result in either a balanced, euploid gamete (center); or imbalances. [Adapted from Grell ]

Figure 3. Potential genetic and environmental influences on gametic aneuploidy

Maternal age has consistently been shown to be associated with an increased risk for gametic aneuploidy, with the mechanism for this association appearing to include aberrant recombination, as well as other factors. In humans, it is speculated that genetic and environmental components impact one's risk for producing aneuploid gametes, with epigenetic changes acquired over time potentially serving as a bridge for these influences. Genes that have been implicated to contribute to aneuploidy (either through mutation or epigenetic alterations) include those involved with chromatid cohesion, meiotic and spindle checkpoints; repair; centrosome function/duplication; and/or recombination. Chromatin organization (heterochromatin versus euchromatin) has been conjectured to influence a chromosome's propensity for gametic aneuploidy and may be influenced by epigenetic changes, but could also illicit epigenetic alterations (hence, the two headed arrow). Heterochromatin may directly impact the frequency of aneuploidy (possibly by compromising the fidelity of the spindle attachments and replication/pairing processes), or its purported role may result from perturbations in recombination, which, in turn, could lead to aneuploidy.

Figure 4. Micronuclei as seen following spectral karyotyping (SKY) and FISH using a pantelomeric/pancentromeric probe

The majority of micronuclei contain chromatin from a single chromosome, as shown in the spectral (a) and classified (b) images of a binucleate having 2 micronuclei, one containing chromatin from chromosome 1 (yellow; right) and one containing chromatin from chromosome 13 (red; lower left). The majority of micronuclei also contain telomeric (red) and centromeric (green) signals (c), suggesting that an intact chromosome/chromatid is present in the micronucleus. The micronucleus shown in (c) has 2 telomeric signals (red) and 1 centromeric (green) signal.

Figure 5. Potential genetic and environmental influences on somatic aneuploidy

*Acquired aneuploidy frequencies reflect contributions from both genetic (65% of variance) and environmental (35% of variance) factors []. Genes that have been implicated to contribute to acquired aneuploidy (either through mutation or epigenetic alterations) are similar to those associated with constitutional aneuploidy and include genes influencing chromatid cohesion, meiotic and spindle checkpoint function; DNA repair; centrosome function/duplication; histone modification; and microRNAs. Heterochromatin-rich chromosomes have been reported to have increased frequencies of aneuploidy (primarily loss). The presence of heterochromatin in somatic cells has been speculated to be influenced by epigenetic changes, but changes in heterochromatin could also illicit epigenetic alterations (demonstrated with a two-headed arrow). Alterations in heterochromatin may directly impact the frequency of aneuploidy (potentially by compromising the fidelity of the spindle attachments and replication/pairing processes). Telomere attrition has also been suggested to lead to aneuploidy. Telomere shortening would reduce the amount of heterochromatin present in the telomeric region, and could lead to an epigenetic change by altering the chromatin conformation which, in turn, could allow for the expression of a gene(s) that would typically be silenced. Telomeres might also have a direct influence on aneuploidy which may be implemented through perturbations in alignment/somatic pairing/chromosomal rearrangements, as well as other potential mechanisms. In contrast to constitutional aneuploidy, the role of advancing age on autosomal acquired aneuploidy is uncertain. Age effects have been denoted for a subset of chromosomes, and, when present, may have direct influences on aneuploidy, or indirect influences (for example, increased age leads to telomere shortening, which, in turn, could predispose to aneuploidy).